Hepatitis C virus (HCV) is a major cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma in the US. The mechanism by which HCV, an RNA virus, persists in the host hepatocyte, evades the host immune response, and causes cancer is unclear. We have recently found that the E2 envelope protein of HCV can activate the transcription of the cellular grp78 and grp94 genes, possibly by a stale interaction with Gro78 (BiP0. Since increased cellular levels of Grp78 or Grp94 have been found to protect the cell against killing by cytotoxic T- lymphocytes and increase the tumorigenicity of transformed cells, our findings point to a possible mechanism for the pathogenesis of HCV- induced chronic infection and carcinogenesis. Indeed, we have obtained preliminary evidence that HCV E2 protein protects against cell death. Therefore, we wish to extend our results to study the mechanism by which E2 protein activates Grp78 expression, to confirm the effect of E2 protein on cell death, and to probe the connection between the two phenomena. Our proposed experiments may provide new insights on how HCV causes liver diseases, and possibly point towards novel avenues of therapy against this important emerging pathogen.